This is an application for a Mentored Clinical Scientist Career Development Award (K08) for Naveen Gupta, MD, a senior postdoctoral fellow in Pulmonary and Critical Care Medicine at the University of California, San Francisco. Dr. Gupta is beginning his career as a young investigator in the field of acute lung injury and has a well-defined interest in the application of cell based therapy for experimental acute lung injury. In this application, Dr. Gupta proposes to study the therapeutic and mechanistic effects of mesenchymal stem cells (MSC) in mouse models of acute lung injury. In Aim 1, the therapeutic effects of MSC will be assessed by the ability of MSC to improve survival and decrease the severity of lung injury. In Aim 2, the mechanistic basis for the MSC effects will be tested by using a combination of gene knockout mice, pharmacologic inhibitors, and siRNA methods. Dr. Gupta postulates that MSC will improve survival and reduce the severity of experimental acute lung injury by (1) shifting the balance from a pro- to an anti-inflammatory response to the inciting cause of lung injury, and (2) the elaboration of growth factors that will improve the function of the alveolar epithelium. In Aim 3, the basic biology of MSC will be investigated with the use of DMA microarray experiments, that will also provide information on novel pathways by which MSC protect against acute lung injury. In addition, in Aim 3, Dr. Gupta will develop strategies to improve upon the MSC population used in order to enhance their biologic effects. This will include selecting for a homogenous, multipotent population of MSC with the aid of recently discovered cell surface markers. The information obtained from the execution of the experiments proposed in this application will shed new light on the biology of MSC as well as their potential to treat experimental acute lung injury. This may then open the possibility of using cell based therapy for clinical acute lung injury, a common form of acute respiratory failure with a mortality of 30- 40% even with the best supportive care. To achieve the goals of this proposal, Dr. Gupta has assembled an expert scientific advisory committee who will oversee his research, and has developed a comprehensive educational plan to enrich his scientific knowledge base. The Cardiovascular Research Institute and the University of California, San Francisco are committed to developing the academic career of Dr. Gupta as a successful independent investigator.